Oxytocin is a naturally occurring nine-amino acid neuropeptide that is primarily produced in the paraventricular and supraoptic nuclei of the mammalian hypothalamus. It is released in to the central nervous system via distributed neural pathways and in to peripheral circulation via the posterior pituitary. The intramuscular injection or intravenous infusion of synthetic oxytocin (Pitocin®) is currently approved in the U.S. to produce or improve uterine contractions to facilitate vaginal delivery and to control postpartum hemorrhage. Intranasal oxytocin (Syntocinon®) had been approved in the U.S. for stimulating milk letdown to facilitate breast-feeding from 1960 until 1997. While the nasal spray of Syntocinon® was withdrawn from the U.S. market at the request of the manufacturer, intranasal oxytocin is still marketed outside of the United States in countries such as Switzerland, Portugal, or Brazil. Use of oxytocin peptides in treatment of pain such as headache pain by intranasal administration has recently been demonstrated. See WO 2007/025249 A2 and WO 2007/025286 A2, the disclosures of which are incorporated herein by reference.
Pain is a perception mediated, in part, by the activation of certain brain structures. Pain is usually initiated when specialized neurons, termed nociceptors, which innervate the skin or other peripheral tissue, are activated by mechanical, thermal, chemical or other noxious stimuli. Pain is also experienced when peripheral or central neuronal structures involved in the processing of pain become hyperactive, e.g. as a result of trauma, ischemia or inflammation. Other causes of pain include disease-specific processes, metabolic disturbances, muscle spasm, and the onset of a neuropathic event or syndrome. Despite a wide range of available medical treatments including non-opioids (such as acetaminophen and non-steroidal anti-inflammatory drugs or NSAIDs), opioids, and co-analgesics (e.g. gabapentin), pain continues to afflict millions of individuals in the US alone and remains a profound burden to patients, health care, and business.
Oxytocin has been shown to reduce pain, in particular chronic pain, associated with the trigeminal nerve, such as trigeminal neuralgia and migraine headache. Human clinical trials have demonstrated efficacy of intranasal oxytocin in treating migraine headache. However, these trials have shown that the latency to analgesia caused by nasal oxytocin is around 2 hours, with the maximal analgesic effect not occurring until about 4 hours after dosing. Thus, there exists a need for an oxytocin peptide formulation capable of faster on-set of the analgesic effect.